The objective of this research is to gain knowledge into the mechanism(s) by which the proliferation of hepatocytes is regulated. This objective will be approached by two routes: 1) study of the occurrence and nature of systemic regulatory influences (especially humoral influences) and 2) examination of the mechanism of action of systemic regulatory influences at tissue and cellular levels. The proposed project utilizes studies on whole animals, isolated-perfused livers, liver tissue cultures, and isolated hepatocyte nuclei. By integrating studies on proliferative functions at various levels of cell and tissue organization we hope to develop more precise insight into the origin and composition of feedback mediators involved in the control of hepatocytic proliferation and into the cellular loci at which these substances act.